Nitric oxide (NO) plays a central role in a number of biological processes such as infection, vasodilation, angiogenesis, and modulation of wound healing (Fang, 1999; Frank et al., 2002; Liew et al., 1991; Rizk et al., 2004; Weller et al., 2001). As an example, a disturbing trend in the treatment of superficial infections is increasing antibiotic resistance among staphylococcal isolates, resulting from current antibiotic pressure. Today, less than 5% of clinical isolates remain sensitive to penicillin (Smith et al., 1999). In the 1980s, methicillin-resistant S. aureus (MRSA) emerged as a prominent hospital-based infection stimulating an increase in the use of vancomycin. A 1997 survey by the Center for Disease Control (CDC) showed that the proportion of methicillin-resistant isolates with sensitivity only to vancomycin increased from 22.8% in 1987 to 56.2% in 1997. Conventional antibacterial treatments for wound infection are becoming less effective not only due to the emergence of antibiotic-resistant strains but also due to the avascular nature of extensive wounds. Many virulent bacteria such as the Staphylococci secrete polymeric materials after association to form protective coatings known as biofilms. The biofilm further impedes the activity of the host defenses and standard antibiotic therapy. Together, these confounding factors impede the effect of systemically administered antibiotics (Costerton et al., 2001).
The body naturally combats infection through numerous biological mechanisms. One such mechanism is the production of nitric oxide (NO) (FIG. 11). NO is produced enzymatically by any of three distinct nitric oxide synthases (NOS) via L-arginine conversion. Each isoform differs considerably in its pattern of expression and regulation. The isoforms of NO are synthesized and released by various cells resident in the skin such as nielanocytes, adipocytes, endothelial cells, macrophages, neutrophils, fibroblasts, and keratinocytes (Heck et al., 1992; Ivanova et al., 1997; MacMicking et al., 1997). The chemical reactivity of NO in the living system is diverse and extensive. The electronic make up of NO allows for diverse interactions with numerous molecular agents. Because NO is lipophilic, readily crossing most natural barriers, it can reach most target cells with relative ease (Subczynski et al., 2000). NO can diffuse along its concentration gradient, permitting it to rapidly move from cell to cell independent of receptors and channels. Because of its high reactivity and short half-life, NO action and biological impact is determined by its rate of formation. Furthermore, because NO is rapidly scavenged by hemoglobin, its site of action is typically very local with respect to where it is generated. However, despite the wide spread therapeutic promise of gaseous NO (gNO), a practical gNO delivery system for most potential applications has yet to emerge.